DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of PCT/US2021/022011 filed March 11, 2021, which claims the benefit of US Provisional Application No. 62/987,872 filed March 11, 2020. All claims have been given an effective filing date of March 11, 2020.
Election/Restriction
Applicant's election without traverse of Group I (Claims 1, 4-11, and 20-24) and species election of A) para-acetyl phenylalanine and B) skin cancer in the reply filed on August 15, 2025 is acknowledged.
Claims 25-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 15, 2025.
Claim Status
Claim listing filed on April 3, 2023 is pending. Claims 2-3 and 12-19 are canceled. Claims 1, 4-11, and 20 are amended. Claims 21-30 are new. Claims 25-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions. Claims 1, 4-11, and 20-24 are examined upon their merits.
Information Disclosure Statement
No information disclosure statement has been filed.
Sequence Compliance in Drawings
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825. Specifically, no sequence identification has been provided for the amino acid sequences presented in Figures 5-6 of the drawings. MPEP § 2412.04 states that where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a)), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a)) in the Brief Description is clear.
Should Applicant choose to correct the drawings, corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant is reminded to comply with sequence rules as stated in MPEP§ 2422 and review the specification to ensure the application is in full sequence compliance in response to this action.
Claim Objections
Claims 10-11 are objected to because of the following informalities: “one or more PEG molecule” should recite “one or more PEG molecules” as molecules is originally presented in Claim 1. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-5, 10-11, and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites an IL-2 polypeptide comprising “one or more amino acid substitutions at selected positions within SEQ ID NO: 2.” There are no limitations as to how many substitutions can be made or which amino acids are substituted which results in a genus of possible IL-2 substitutions. Claims 4-5, 10-11, and 20-22 depend from Claim 1 and do not further limit the genus of IL-2 substitutions.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of the claimed genus of IL-2 substitutions, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the instant case, the specification teaches two IL-2 substitutions (excluding the non-natural amino acid incorporated at position 42): R38A and P65R (Examples 13 and 15-16). IL-2 polypeptides comprising R38A and/or P65R mutations are shown to have reduced binding to IL-2Rα (Examples 13 and 15). However, two substitutions are not sufficient to describe the genus of IL-2 substitutions encompassed by the claims.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of IL-2 substitutions, the specification does not provide adequate written description of the claimed genus. Therefore, in view of the case law directed to an appropriate number of representative species, claims 1, 4-5, 10-11, and 20-22 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1, 4-5, 10-11, and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabled for IL-2 substitutions at positions 38 and/or 65, does not reasonably provide enablement for the genus of IL-2 substitutions at one or more positions (Claim 1). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
Claim 1 recites an IL-2 polypeptide comprising “one or more amino acid substitutions at selected positions within SEQ ID NO: 2.” There are no limitations as to how many substitutions can be made or which amino acids are substituted which results in a genus of possible IL-2 substitutions. As understood with the broadest reasonable interpretation, every amino acid residue at positions 1-133 of SEQ ID NO: 2 could be substituted as long as a non-natural amino acid is incorporated at position 42.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Yue-Sheng US 2022/0235109 (effectively filed Dec. 2019) teaches that residues R38 and P65 are known to be at the binding interface of IL-2 with IL-2Rα, and introducing one or two amino acid substitutions at these relevant residues can reduce or abolish binding to IL-2Rα (paragraph [0144]). Yue-Sheng specifically teaches the amino acid substitutions R38F, R38G, R38A, P65G, P65E, P65H, P65R, P65A, P65K, P65N, and P65Q (Table 2). Therefore, Yue-Sheng provides enablement for IL-2 substitutions at positions R38 and/or P65 that are known to diminish binding to IL-2Rα which is the same disclosed utility of the instant IL-2 polypeptide (paragraph [0539]).
However, the art does not provide enablement for an IL-2 polypeptide comprising any amino acid substitution at any position and in any combination. Given that structure dictates function, the claimed genus of IL-2 substitutions that varies widely in structure also varies widely in function and is not predictable by the state of the prior art. There is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of IL-2 substitutions claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the invention are preserved (reduced or abolished binding to IL-2Rα).
Level of skill in the art:
The level of skill would be high encompassing polypeptide design, polypeptide purification, binding assays, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches two IL-2 substitutions (excluding the non-natural amino acid incorporated at position 42): R38A and P65R (Examples 13 and 15-16). IL-2 polypeptides comprising R38A and/or P65R mutations are shown to have reduced binding to IL-2Rα (Examples 13 and 15). However, two substitutions are not sufficient to describe the genus of IL-2 substitutions encompassed by the claims. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of IL-2 substitutions to encompass the claimed genus.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the IL-2 substitutions encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims.
The instant specification does not enable the invention to make and use the entire genus of IL-2 substitutions encompassed by Claim 1; therefore, Claims 1, 4-5, 10-11, and 20-22 are rejected.
Note, the application is enabled for the genus of non-natural amino acids and the genus of PEG molecules claimed, because site-specific incorporation of PEG molecules using nonnatural amino acid mutagenesis was well understood in the art prior to the time of filing as evidenced by Shozen et al. Bioorg Med Chem Lett. 2009; Graaf et al. Bioconjug Chem. 2009; Voloshchuk et al. Mol Biosyst. 2009; Greenwald RB. J Control Release. 2001; and Gupta et al. J Cell Commun Signal 2018.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-6, 10-11, and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ptacin WO 2019/028419 as evidenced by Ferrara FEBS Lett. 1987.
In regard to Claims 1, 4-6, 10-11, and 21, Ptacin teaches an IL-2 conjugate comprising an IL-2 polypeptide that has an unnatural amino acid at position F42 corresponding to SEQ ID NO: 1, wherein a conjugating moiety is bound to the unnatural amino acid and the conjugating moiety is a PEG molecule (paragraph [0005]). Ptacin SEQ ID NO: 1 is 100% identical to instant SEQ ID NO: 2. The IL-2 conjugate has reduced binding to IL-2Rα but does not impair binding with IL-2Rβγ (paragraph [0007], lines 1-6). Ptacin specifically exemplifies an IL-2 comprising the unnatural amino acid N6-azidoethoxy-L-lysine (AzK) at position F42 wherein a 30kDa linear PEG is bound to the unnatural amino acid (paragraph [0375], Tables 1 and 4). While AzK was used in the examples, Ptacin teaches that other unnatural amino acids can be substituted such as p-acetyl-L-phenylalanine (paragraphs [0005] and [0084]). The IL-2 can comprise one or more substitutions to other naturally occurring amino acids at positions R38 and/or P65 (paragraphs [0075] and [0077]).
In regard to Claim 20, Ptacin teaches that the IL-2 incorporating the unnatural amino acid is produced in a host cell, preferably a mammalian cell such as Chinese hamster ovary cells (CHO) (paragraphs [0319]-[0320]). By producing the IL-2 in mammalian cells such as CHO, Ptacin implicitly teaches producing IL-2 in its glycosylated form. As evidenced by Ferrara FEBS Lett. 1987, recombinantly producing IL-2 in CHO cells results in IL-2 with posttranslational glycosylation similar to natural IL-2 (abstract and page 51).
In regard to Claim 22, Ptacin teaches that the PEG conjugation moiety is attached to the IL-2 via an oxime (paragraph [0194]).
Therefore, Claims 1, 4-6, 10-11, and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ptacin.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 7-9 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ptacin WO 2019/028419 as evidenced by Ferrara FEBS Lett. 1987 as applied to Claims 1, 4-6, 10-11, and 20-22 above, and further in view of Yue-Sheng US 2022/0235109 (effectively filed Dec. 2019).
The teachings of Ptacin as they apply to Claims 1, 4-6, 10-11, and 20-22 are outlined in the rejection above. Ptacin teaches an IL-2 conjugate that has reduced binding to IL-2Rα but does not impair binding with IL-2Rβγ (paragraph [0007], lines 1-6), wherein the IL-2 comprises substitutions at R38 and/or P65 to a different naturally occurring amino acid, specifically listing P65R (paragraphs [0075] and [0077]). By preferentially binding IL-2Rβγ over IL-2Rα, the IL-2 conjugate expands CD4+, CD8+, and natural killer cells over Treg cells which is advantageous in cancer therapy (paragraphs [0012]-[0013]). Ptacin fails to distinguish a motivation to select P65R from the P65 mutations listed in paragraph [0077] and fails to teach R38A as required by Claims 7-9 and 23-24.
Yue-Sheng teaches an IL-2 variant comprising SEQ ID NO: 3 having one or more mutations selected from substitutions comprising R38A and P65R wherein the IL-2 variant demonstrates reduced binding to IL-2Rα yet retains the ability to bind and activate the IL-2Rβγ complex (Claims 40 and 42 and Table 2). Note, SEQ ID NO: 3 and instant SEQ ID NO: 2 are identical, only differing by a C125A mutation that is well understood in the art in recombinant IL-2. Yue-Sheng teaches that amino acid substitutions to one or two relevant residues at the interface of IL-2 and IL-2Rα (including residues R38 and P65) were introduced to reduce or abolish binding to IL-2Rα (paragraph [0144]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the known IL-2 mutations taught by Yue-Sheng to the IL-2 conjugate taught by Ptacin. Ptacin specifically teaches that the IL-2 can be mutated at residues R38 and P65 and that reduced binding to IL-2Rα is preferable for therapeutic applications. Yue-Sheng teaches that the specific mutations R38A and P65R are known to reduce IL-2 binding to IL-2Rα. The substitutions could be made by one of ordinary skill to yield predictable results (IL-2 with reduced binding to IL-2Rα). The motivation to make the R38A and P65R mutations that reduce binding to IL-2Rα is to expand CD4+, CD8+, and natural killer cells over Treg cells which is advantageous in cancer therapy (Ptacin paragraphs [0012]-[0013]).
Double Patenting
No double patenting rejections are made in view of US Patent No. 12,049,485 or US App. No. 18/741,621 because the patented and copending claims are directed to an IL-2 conjugate comprising an IL-2 polypeptide having a non-natural amino acid at position 45 and no further amino acid substitutions, which is patentably distinct from the instant claims.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675